Technical Field This disclosure relates to the field of chemotherapy treatment of patients having neoplastic disease. In particular, this disclosure relates to chemotherapy employing halogenated analogs of thymidine (abbreviated “HAT”).
Background Information
A. Pain
Cancer-related pain, and cancer symptoms broadly, are generally accepted to result from uncontrolled growth and metastasis of neoplastic cells (tumor cells) within the body. The broad consensus on cancer-related pain management is reflected in the information provided on the following websites:    a) www(dot)cancer(dot)gov/cancertopics/pdq/supportivecare/pain/Patient/page4;    b) www(dot)mayoclinic(dot)org/diseases-conditions/cancer/in-depth/cancer-pain/art-20045118;    c) www(dot)sirweb(dot)org/patients/bone-cancer/iv. www(dot)cancer-pain(dot)org/.
In brief, currently accepted methods for treating pain and other symptoms caused by neoplastic cell growth and metastases involve a “3 tier pyramid” in which the medication of last resort is morphine and other synthetic and natural opioid-related drugs which relieve pain through opioid receptor binding in nerve cells that transmit and/or receive pain signals. Patient-acquired resistance limits the long-term effectiveness of morphine and related drugs. In addition, side effects can affect consciousness, normal day-to-day activity, and potentially lead to lethality.
B. Cell-Kill Strategy for Cancer Therapy
It is generally accepted that uncontrolled tumor growth results mainly from uncontrolled replication of neoplastic cells. Currently accepted methods for reducing neoplastic cell replication involve “cell-kill” (cytolytic) agents including but not limited to ionizing radiation and chemotherapy agents that were originally developed in the 1950s many of which persist in present day practice. Because replicating cells are generally considered to be the principal killing targets for such cell-kill methods, the high rate of cell replication in tumors is generally believed to elevate tumor cell-kill rates. Limitations to the extended, long-term use of cell-kill agents are due principally to: (a) debilitating side-effects on non-neoplastic (normal) cells and tissues (including both replicating and non-replicating cells), and; (b) resistance acquired by surviving neoplastic cells to the effects of cell-kill chemotherapy drugs. In some cases, alternative cell-kill drugs, alone or in combination, may be employed to mitigate acquired resistance.
C. Abnormal Neoplastic Cell Behavior
Neoplastic cells share a common set of abnormal cellular behaviors that distinguish them from normal, non-neoplastic cells. The abnormal behavior of neoplastic cells in culture (in vitro) are broadly correlated with the abnormal behavior of tumor cells within the body. Abnormal neoplastic cell behaviors in culture include, but are not limited to:                1. Uncontrolled Neoplastic Cell Replication        Uncontrolled neoplastic cell replication occurs without regard to cell-intrinsic and cell-extrinsic controls that typically govern replication of normal cells in the body's tissues and organs. Uncontrolled neoplastic cell replication is a primary cause of tumor growth. The impingement of uncontrolled tumor growth upon neighboring tissues is a principal cause of cancer-associated pain and other discomfort.        2. Unanchored Neoplastic Cell Survival        Neoplastic cells in culture are able to survive without being anchored (attached) to a substrate, while normal cells typically die, through autonomous mechanisms, if unable to attach to a compatible substrate. Neoplastic cells can also survive and replicate in soft agar where no compatible surface or substrate is available for attachment, a condition in which normal cells cannot survive.        Substrate-attachment and extensive cell-cell attachments and interactions are also the general rule for cells in the tissues of the body except for circulating cells of the blood and lymphatic spaces which are variously adapted to continuous motility.        3. Absence of Contact Inhibited Neoplastic Cell Motility and Replication        Expansion and movement of normal cells in a culture dish are restricted to the plane of the substrate on the dish surface and proceed through extension of membrane filopodia which form complex cell-cell contacts with the surface membranes of neighboring cells. Such cell-cell contacts result in the inhibition of cell replication among contacted cells. Furthermore, movement of normal cells or their filopodia over the boundaries of neighboring cells rarely occurs.        Neoplastic cells, by contrast, typically pile up on one another in culture dishes due to the absence of contact inhibition and substrate-attachment-dependence. Comparable piling up of cells in culture does not occur with normal (non-neoplastic) cells.        4. Uncontrolled Tumor Growth and Expansion (In Vivo)        It is generally accepted that neoplastic tumor growth is the result of uncontrolled replication of tumor cells that is unconstrained by various cellular mechanisms, including but not limited to, contact inhibition or substrate-attachment-dependence.        5. Metastasis or Spread of Tumor Cells (In Vivo)        It is generally accepted that metastasis, or the spread of malignant tumor cells in the patient body, is dependent upon the movement and migration of neoplastic cells from their site of origin to new sites in the body [http://www(dot)cancer (dot)gov/cancertopics/factsheet/Sites-Types/metastatic]. The absence of substrate-attachment-dependence is a neoplastic cell characteristic that is generally believed to permit metastatic cells to survive and replicate during migration.        6. Tumorigenicity (In Vitro and In Vivo)        Tumorigenicity, in general, refers to the ability of tumor cells to expand and colonize new sites in the body of a patient or an experimental animal. It is generally believed that tumorigenicity reflects, to an unquantifiable degree, a summation of the abnormal neoplastic behaviors outlined above.D. Poly(ADP-ribose) Polymerase 1 (PARP1)        
PARP1[poly(ADP-ribose) polymerase 1(E.C.2.4.2.30)] is a nuclear enzyme that catalyzes the synthesis of the third natural form of nucleic acid, comprising chains of adenosine residues that are oligomeric (2-20 residues) or polymeric (>20 residues) and which are generally collectively referred to here and elsewhere as “poly(ADP-ribose)” (PAR). Initiation of PAR synthesis involves covalent attachment of a single ADP-ribose residue, derived from cleavage of its substrate molecule, NAD+ (nicotinamide adenine dinucleotide, the ubiquitous metabolic coenzyme), to an amino acid residue within a polypeptide chain of a “target” protein. PARP1 is one member of a family of ADP-ribosyltransferase enzymes (ARTS) that share a structurally similar NA+ (substrate) binding site. Proteins which are trans-modified by PARP1 include but are not limited to histone proteins and regulatory proteins. An enzymatically active PARP1 dimer may also auto-modify by synthesizing a PAR chain attached to one dimer partner. PAR chain elongation involves serial addition of adenine residues derived from NAD+ substrate molecules to generate a linear oligonucleotide chain typically 20 or fewer residues in length but which may be longer and/or branched in some instances. PAR chains are also subject to degradation by another cellular enzyme, Poly(ADP-ribose)glycohydrolase (PARG), which can remove PAR chains from proteins and release ‘free’ oligomeric PAR chains that are no longer covalently bound to a target protein. Proteins and other macromolecules that bind free PAR chains non-covalently may also be structurally and/or functionally altered in an unknown manner.
Chemotherapy Through Inhibition of PARP1 Enzymatic Activity
Clinical trials have employed PARP1 inhibitors to treat neoplastic and other disregulative diseases. Numerous USPTO applications propose, as part of a cancer treatment regimen, the use of one or more PARP1 inhibitors to inhibit repair of DNA strand breaks resulting from either introduced DNA-damage agent(s) or from intrinsic cause(s). A small number of USPTO applications have proposed using PARP1 inhibition-alone for anti-cancer chemotherapy.
PARP1, Molecular Information Link:
                http://www(dot)brenda-enzymes(dot)org/enzyme.php?ecno=2.4.2.30.E. Halogenated Analogs of Thymidine (HAT)1. HAT and HAT-DNA; Definitions        
Bromodeoxyuridine and iododeoxyuridine are halogenated analogs of thymidine (HAT) because, in biological systems, each mimics thymidine, a natural metabolite. HAT compounds (and related compounds including, but not limited to, bromouracil and iodouracil) enter human cells and other animal cells by passive and active transport. During cell replication, and other cellular processes involving DNA synthesis, HAT compounds are efficiently incorporated into DNA in place of the natural precursor, thymidine. DNA containing HAT is referred to as “HAT-DNA” in this document.
Due to its ease of incorporation into DNA, and sensitive methods available to detect such incorporation, HAT compounds are in broad use world-wide as markers to detect HAT-DNA in purified systems, as well as in living cells, tissues and organs.
2. HAT Anti-Neoplastic Effects Widely Attributed to HAT-DNA
Anti-neoplastic effects result when HAT compounds are added to the culture medium of a wide variety of cultured neoplastic cells. HAT anti-neoplastic effects on neoplastic cells include but are not limited to:    a. arrest of uncontrolled neoplastic cell replication;    b. neoplastic cell-survival becoming anchorage-dependent; and    c. neoplastic cell death and disintegration after HAT exposure for extended periods.
These and other anti-neoplastic effects of HAT that have been observed in cultures of neoplastic cells have been widely and generally attributed to HAT-DNA despite the absence of any generally accepted evidence or hypothesis that explains how HAT-DNA might exert any such anti-neoplastic effect including, but not limited to, those outlined above.
3. HAT-DNA and Adjuvant Therapy
HAT compounds have also been widely employed as adjuvants intended to increase cell-sensitivity to the DNA-damaging effects of radiation therapy and/or by DNA-damaging drug chemotherapy. Such usage is based upon the generally accepted rationale that the DNA in neoplastic tumor cells is more easily broken during therapy with DNA damage agents (radiotherapy and/or chemotherapy) when some or all thymidine nucleotide positions in their DNA are occupied by HAT nucleotides (HAT-DNA).
4. HAT-DNA:
The Sole Cellular Target of Current HAT-Based Chemotherapy Methods
In conclusion, in all current antineoplastic concepts, explanations and applications of HAT chemotherapy, DNA is the exclusive cellular molecule targeted and all therapeutic uses are based solely on the central concept that the presence of HAT nucleotides in neoplastic cell DNA alters its physical and biological properties in a manner that has antineoplastic effects for therapeutic purposes.
The term “HAT-DNA”, as used in this document, refers specifically to DNA molecules that have incorporated bromodeoxyuridine and/or iododeoxyuridine nucleotides in place of thymidine nucleotides either partially or completely. This term is also used more broadly to describe, distinguish or identify ideas, hypotheses, treatments and/or therapies that are based upon HAT-DNA ideation, concept, or model.